This invention relates to a novel peptide and, more particularly, to a pentadecapeptide that is an endogenous regulator of intestinal guanylate cyclase.
Guanylate cyclase is composed of a group of proteins that share structural characteristics relative to the enzymatic function of producing cyclic GMP, but differ quite remarkably in their selective activation by ligands. The three major forms of guanylate cyclase are the soluble, particulate, and intestinal (cytoskeletal-associated particulate or STa-sensitive) with each of these forms regulated by different ligands (1, 2). Activation of the soluble guanylate cyclase occurs in response to nitric oxide (EDRF), while activation of the particulate enzyme occurs in response to the natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide) (1, 2). An endogenous activator of the intestinal guanylate cyclase has not previously been identified, however the heat stable enterotoxin from E. coli is known to selectively activate this form of the enzyme (3,4). This form of the enzyme is predominantly found in the intestinal epithelial cells with the largest number of receptors oriented towards the lumen (1,2). Recently, the intestinal form of guanylate cyclase has been cloned and expressed from rat small intestinal mucosa (5). This enzyme is characterized by an extracellular receptor binding region, a transmembrane region, an intracellular protein kinase-like region and a cyclase catalytic domain (5).
Pathogenic strains of E. coli and other bacteria produce a family of heat stable entertoxins (STs) that activate intestinal guanylate cyclase. STs are acidic peptides 18-19 amino acids in length with six cysteines and three disulfide bridges that are required for full expression of bioactivity (6). The increase of intestinal epithelial cyclic GMP elicited by STs is thought to cause a decrease in water and sodium absorbtion and an increase in chloride secretion (7, 8). These changes in intestinal fluid and electrolyte transport then act to cause secretory diarrhea. In developing countries, the diarrhea due to STs is the cause of many deaths, particularly in the infant population (9). STs are also considered to be a major cause of traveler's diarrhea in developed countries (10). STs have also been reported to be a leading cause of morbidity in domestic animals (11).